(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
(19) World Intellectual Property Organization
International Bureau
(43) International Publication Date
12 September 2002 (12.09.2002)
mm
PCT
llll II I Ihll 1 1 I'll 11:11' II II I'LL IHII III
(10) International Publication Number
WO 02/071044 Al
(51) International Patent Classification 7 : G01N 21/78,
33/52, 35/02
(21) International Application Number: PCT/US02/05091
(22) International Filing Date: 28 February 2002 (28.02.2002)
(25) Filing Language: English
(26) Publication Language: English
(30) Priority Data:
09/794,044
28 February 2001 (28.02.2001) US
(71) Applicant (for all designated States except US): HOME
DIAGNOSTICS, INC. [US/US]; 2400 N.W. 55th Court,
Fort Lauderdale, FL 33309 (US).
(72) Inventors; and
(75) Inventors/Applicants (for US only): MODZELEWSKI,
Brent, E. [US/US]; 13 Red Barn Lane, Brookfield, CT
06804 (US). GILMOUR, Steven, B. [US/US]; 532
Navarre Avenue, Coral Gables, FL 33134 (US).
(74) Agents: GARRETT, Arthur, S. et al.; Finnegan, Hen-
derson, Farabow, Garrett & Dunner, L.L.R, 1300 I Street,
N.W., Washington, DC 20005-3315 (US).
(81) Designated States (national): AE, AG, AL, AM, AT, AU,
AZ, BA, BB, BG, BR, BY, BZ, CA, CH, CN, CO, CR, CU,
CZ, DE, DK, DM, DZ, EC, EE, ES, FI, GB, GD, GE, GH,
GM, HR, HU, ID, IL, IN, IS, JP, KE, KG, KP, KR, KZ, LC,
LK, LR, LS, LT, LU, LV, MA, MD, MG, MK, MN, MW,
MX, MZ, NO, NZ, OM, PH, PL, PT, RO, RU, SD, SE, SG,
SI, SK, SL, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ,
VN, YU, ZA, ZM, ZW.
(84) Designated States (regional): ARIPO patent (GH, GM,
KE, LS, MW, MZ, SD, SL, SZ, TZ, UG, ZM, ZW),
Eurasian patent (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM),
European patent (AT, BE, CH, CY, DB, DK, ES, FI, FR,
[Continued on next page]
(54) Title: DISTINGUISHING TEST TYPES THROUGH SPECTRAL ANALYSIS
©
©
ri
o
(57) Abstract: A method and apparatus for
. automatically selecting test types for an analytical meter
system (10) based on the insertion into the meter of a
test element (30). The test element can be an analytical
element, formed by a test strip with control fluid
applied thereto; or a standard element, or a standard
strip exhibiting known optical properties. By inserting
the test element into the analytical meter system,
optical properties are measured and the existence of
relationships between the measurements are ascertained.
WO 02/071044 Al 1 0111 IDIIIII fl Ifirif lim Off I II flf Hill if If I Iflil Iffll IIM Illf IW Ifl fill Ifll All
GB, GR, IE, IT, LU, MC, NL, PT, SB, TR), OAPT patent
(BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, ML, MR,
NE, SN, TD, TG).
Published:
— with international search report
— before the expiration of the time limit for amending the
claims and to be republished in the event of receipt of
amendments
For two-letter codes and other abbreviations, refer to the "Guid-
ance Notes on Codes and Abbreviations" appearing at the begin-
ning of each regular issue of the PCT Gazette.
WO 02/071044 PCT/US02/05091
DISTINGUISHING TEST TYPES THROUGH SPECTRAL ANALYSIS
DESCRIPTION OF THE INVENTION
Field of the Invention
The present invention relates generally to methods and apparatus for
determining the test type to be performed on various types of test elements. More
particularly, this invention provides methods for distinguishing between different types of
test elements, including analytical test strips with fluid samples applied to them,
analytical test strips with control solution applied to them, and standard strips as
measured by a reflectance-type testing device.
Background of the Invention
Monitoring analytes such as glucose, cholesterol, intoxicants, and other
constituents is frequently desirable in fluids, such as blood, plasma, blood serum, saliva,
urine, and other biological fluids. In healthcare applications, such monitoring affords the
opportunity to make rapid diagnoses of a patient's condition and to take prophylactic or
therapeutic measures necessary for maintaining proper health.
One such healthcare application that has benefited tremendously by analyte
monitoring in recent years is the treatment of diabetes. Diabetics suffer from an
impaired ability to regulate glucose levels in their blood. As a result, diabetics can have
abnormally high blood sugar levels known as hyperglycemia. Chronic hyperglycemia
may lead to long-term complications such as cardiovascular disease and degeneration
of the kidneys, retinas, blood vessels and the nervous system. To minimize the . risk of
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such long term complications, diabetics must strictly monitor and manage their blood
glucose levels.
Diabetics that have glucose levels that fluctuate several times throughout the day
require very close blood glucose level monitoring. Close monitoring of blood glucose
levels is most easily obtained when a diabetic is able to monitor their glucose levels
themselves. Many devices currently available allow diabetics to measure their own
blood sugar levels.
Reflectance-based monitors comprise one category of personal, or home-use,
glucose level monitoring devices. These monitors utilize an optical block which accepts
test elements for photometric analysis.
The test elements are usually in the form of test strips, which contain analytical
chemistry,. Conventionally, these test strips are in the form of a disposable diagnostic
test strip containing analytical chemistry upon which a fluid sample is deposited. Once
the user applies the fluid sample to the test strip, and the sample has sufficiently
penetrated the test strip, a chemical reaction occurs in the presence of a target analyte,
e.g., glucose, to cause a change in the optical properties of the test strip. An optical
photometric device then determines the analyte level of the sample by measuring an
optical property, such as the intensity of reflected light at a certain wavelength from the
test strip. For in vitro analysis in healthcare applications, the fluid sample is usually
fresh whole blood. Periodically, however, it is desirable to run a test on a test element
formed by applying a control solution of known analyte concentration to a test strip, in
order to verify that the meter is performing within operational limits. It is also desirable
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for the user to insert a "standard strip", which is a test element that has known optical
properties, in order to verify that the meter is operating within operational limits.
Diagnostic test strips for testing analytes such as glucose levels of blood
samples are well known in the art and comprise various structures and materials. Test
strips typically include single or multi-layered porous membrane arrangements which
receive a blood sample and undergo a change in an optical property, such as a color
change, in response to the interaction of blood glucose with agents/reactants in the
membrane. Examples of such multi-layer strips are described in U.S. Patents
5,296,192 to Carroll and 6,010,999 to Carroll et al., the contents of both of which are
incorporated herein by reference.
Prior to reaching the reactants, a whole blood sample can be filtered to eliminate
potential optical interference by removing erythrocytes, or red blood cells. Some test
strips operate to allow the applied blood sample to migrate to a reaction site in the
membrane where the sample reacts with the agents/reactants, which is located in
downstream capillary relation to the sample application site. The results of the reaction
are often visible as a color change at the reaction site. However, the change may occur
in invisible regions of the electromagnetic spectrum, such as infrared and ultraviolet.
For the purposes of this application, the term "color change" will be understood to
include variations in optical properties throughout the visible and invisible regions of the
electromagnetic spectrum. As noted above, a color change can be correlated to the
amount of glucose in the sample. Home-use glucose measuring devices that use a
reflectance meter to measure the color change of the test strip correlate glucose levels
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to the change in the amount of light reflected from the reaction site of the test strip. As
is well known in the art, strips can be formulated to produce a color change within a
certain spectral region, and the meter designed to photometrically measure reflected,
absorbed or transmitted light at a wavelength sensitive to the color change of the strip.
While the present invention will be described with reference to reflectance based
photometry, it would be known to one having ordinary skill in the art to apply the
features of the invention to absorbance or transmittance based systems.
Desirable for maintaining the accuracy of blood glucose monitoring devices is the
periodic checking of the device to ensure that it is within operational compliance. As
mentioned above, certain periodic standardization tests performed by the user provide
verification of the meter's accurate operation. Accuracy is required by regulatory
authorities for medical devices such as diabetes testing monitors, where a patient's life
can depend on proper operation of the monitoring system.
Common verification techniques are designed to periodically check whether the
monitoring device is operating properly, and thus accurately measuring blood glucose
levels. Verification techniques used in glucose level monitoring devices include
inserting test elements having a known glucose or reflectance value into the monitoring
unit and comparing the measured results with the known values. Test elements having
known glucose levels ("Control Test Elements" hereinafter) are normally prepared by
applying a glucose control solution having a known glucose concentration to a dry test
strip that normally could be used to run a test with blood. The control test element is
then inserted into the monitoring unit and a test is performed and the calculated glucose
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value of the test element is displayed. The calculated glucose value is then compared
with a range of acceptable results provided by the manufacturer for the glucose control
solution. If the results displayed by the device for the control test element fall with an
acceptable range designated for the solution, the device is deemed to be appropriately
functioning ready for testing a blood sample.
Another verification technique commonly used in glucose level monitoring
devices includes inserting a strip with a known reflectance value into the monitoring unit
("Standard Test Element" of "Standard Strip" hereinafter). This standard test element
does not receive a fluid sample, but is rather formed of a one piece rigid or semi-rigid
material such as plastic having known optical properties. The standard reflectance strip
can be stored in a compartment of the monitoring unit so that it is conveniently available
for use throughout the life of the monitoring device. The standard reflectance strip is
inserted into and measured by the device just as other test strips, and the measurement
results are compared with a range of acceptable results provided with standard
reflectance strip. As with the test using the glucose control test element, if the results of
the measurement fall within an acceptable range, the device is ready for testing a blood
sample.
The test run with the standard test element ("Standard Tesf hereinafter) Is
intended to test the performance of the monitoring device only, while the test run with
the control test element ("Control Test" hereinafter) is intended to check the entire
monitoring process including the testing technique of the user. Conventional glucose
monitoring devices are capable of performing both types of calibration techniques and
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will normally include instructions regarding when to initiate each type of calibration
technique.
Of course, the monitoring device must also accept a test element formed by
sample fluid, such as blood, applied to a test strip ("Analytical Test Element"
hereinafter), and run an analytical test thereon to determine analyte concentration
("Analytical Test" hereinafter).
A problem with prior art devices has been that they have typically not been able
to discriminate between the type of test element introduced into the meter, and
therefore the type of test to run, without user intervention. For example, the standard
test is instantaneous and need not ascertain that a reaction on a test strip has run to
completion, as is required in the control test and the analytical test. It is also desirable
that the historical results for all three tests should be stored separately, so that the
user's results from the analytical tests are not mixed in or displayed with the standard
test or control test results.
Conventional methods for differentiating the test type have required the user to
perform an affirmative act, such as pressing a button on the device, to signal to the
device that the test strip inserted includes a glucose control solution and not a blood
sample.
The requirement that a user perform an affirmative act to signal to the monitoring
device the type of sample tested allows the possibility for human error that can
adversely affect the proper storing and monitoring of measurement results, and possibly
the misinterpretation of stored results. For example, if a user were to fail to perform a
6
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required step indicating insertion of a test strip containing glucose control solution, such
as failing to push a button or wait a specified time, the measurement results could be
incorrectly stored in the memory of the device as an actual blood glucose level result,
possibly resulting in, among others, false self-diagnosis of blood sugar levels or
erroneous treatment regimens being prescribed by healthcare professionals.
Another prior art system is a "negative blood" approach, which uses two
wavelengths. In such a system, a secondary LED which measures at a wavelength at
which red blood cells are highly detectable, this measurement is used to formulate a
correction factor used in running the glucose test in whole blood to subtract out optical
interference caused by hemoglobin. This arrangement is usually necessary in
conjunction with single-layer test strips, which are generally unable to adequately
separate hemoglobin from whole blood sample as it flows to the opposite surface where
the colorimetric reaction with the reagent is desired to be measured. If reflection from
this secondary LED is not detected to achieve a certain threshold, that is if there is no
hemoglobin detected, the meter automatically assumes that the test element is a control
element. This methodology is in essence binary, and is limited to the distinction
between "Blood" and "Not Blood;" and is therefore not satisfactory if there are more than
two possibilities.
The difficulties monitoring devices have in properly distinguishing the type of test
element inserted also carries over to distinguishing between insertion of a test strip
having a sample applied thereon, i.e. a control test element or an analytical test
element, and insertion of a standard reflectance strip. Again, conventional monitoring
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devices have the drawback of requiring an affirmative act from the user to signal that a
non-analytical test is being performed by the monitoring device. It is accordingly an
object of the invention to provide a method for automatically distinguishing between the
type of test performed by the device based on the test element inserted by the user,
without the need for any affirmative act by the user.
SUMMARY OF THE INVENTION
In accordance with the invention, a method for automatically selecting test types
in an analytical meter system is described, the method comprising the steps of:
providing a test element, said test element belonging to one of a plurality of test
element types; ' ,
inserting said test element into an analytical meter system;
measuring a first optical property of the test element;
measuring a second optical property of the test element;
distinguishing said test element by identifying a predetermined relationship
between said first and second optical properties;
selecting a test type based at least in part upon the results of said distinguishing
step.
Also described is a meter system for performing one of a plurality of test types on a
test element, where the test element is inserted into the meter system and belongs to
one of a plurality of test element types, the meter system comprising:
a first light emitting diode selectively discharging light at a first wavelength;
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a second light emitting diode selectively discharging light at a second
wavelength;
at least one light detector for measuring light emitted from the first and second -
light emitting diodes and reflected from a test element; and
a processor for distinguishing said test element by identifying a predetermined
relationship between first and second optical properties, and further for selecting a test
type based at least in part upon the results of said distinguishing. '
Additional objects and advantages of the invention will be set forth in part in the
description which follows, and in part will be obvious from the description, or may be
learned by practice of the invention. The objects and advantages of the invention will
be realized and attained by means of the elements and combinations particularly
pointed out in the appended claims. *
It is to be understood that both the foregoing general description and the
following detailed description are exemplary and explanatory only and are not restrictive
of the invention, as claimed.
BRIEF DESCRIPTION OF THE DRAWINGS
The accompanying drawings, which are incorporated in and constitute a part of
this specification, illustrate one embodiment of the invention and, together with the
description, serve to explain the principles of the invention.
Fig. 1 illustrates an analyte meter system according to the present invention;
Fig. 2 illustrates a test strip for receiving a fluid sample and insertion into the
meter system of Fig. 1 , all in accordance with the present invention;
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Fig. 3 illustrates a graph of Reflectance v. Wavelength for an analytical element
formed of blood sample of relatively high glucose concentration applied to the test strip
' of Fig. 2;
Fig. 4 illustrates a graph of Reflectance v. Wavelength comparing the spectral
curve of the analytical element of Fig. 3 with that of a control element formed of control
solution of substantially equal glucose concentration applied to the test strip of Fig. 2;
Fig. 5 illustrates a graph of Reflectance v. Wavelength comparing the spectral
curve of an analytical element formed of blood sample of relatively low glucose
concentration applied to the test strip of Fig. 2, with that of a control element formed of
control solution of substantially equal glucose concentration applied to the test strip of
Fig. 2; and
Fig>6 is a schematic representation of a meter system according to the present
invention.
DETAILED DESCRIPTION OF THE INVENTION
Reference will now be made in detail to an illustrative embodiment of the
invention, which appears in the accompanying drawings. Wherever possible, the same
reference numbers will be used throughout the drawings to refer to the same or like
parts.
With reference to the drawings, Fig. 1 depicts an analyte meter system 10
according to the present invention. Meter system 10 generally includes a hand-held
meter having a housing enclosure 12, power button 14, control buttons 16, 18, liquid
crystal display (LCD) 20, removable test chamber cover or shroud 22 having a test strip
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platform 24 for receiving and testing a multi-layered diagnostic test strip 30, A strip
sensor (not shown) of known configuration is located at a distal end of the strip platform
24 to detect when a test strip 30 has been fully inserted into the device. The test strip
30 contains a reagent that produces a detectable response in proportion to the amount
of a suspected analyte, such as glucose, cholesterol, ketones, theophylline, and
fructosamine, and others. Although the present invention is adaptable for testing
multiple analytes, discussion is directed herein to monitoring glucose levels in whole
blood samples for purposes of describing the instant invention.
Fig. 2 illustrates an enlarged view of diagnostic test strip 30. Test strip 30
generally includes an upper and lower support layer 32, 34, with sample receiving
layers 36 located between the support layers 32, 34. Sample receiving layers 36
include a spreading layer 38 located adjacent upper support layer 32, a separating layer
40, and a semi-porous membrane reagent layer 42 located adjacent lower support layer
34. At least one of the sample receiving layers 36 is pretreated with a dry chemistry
reagent and conditioning solution. Preferably, the membrane 42 and separating layer
.40 are pretreated with the reagent/conditioning solution. The spreading layer 38 may
also be treated. Each layer is positioned in substantially continuous contact with its
adjacent layer as shown in Fig. 2 by adhesives and ultrasonic bonding, or other known
means, to provide a sealed composite structure.
The top and bottom support layers 32, 34 of test strip 30 each define an~aperture
or opening therethrough. These apertures or openings of the test strip 30 are oriented
in vertical alignment with a test window (not shown) located along strip platform 24 (Fig.
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1 ) when properly positioned in meter system 10. The opening in the upper support strip
32 defines a sample receiving port 44 and the opening in the lower support strip 34
defines a reaction viewing port 46. The sample receiving layers 36 are oriented in
vertical alignment with sample receiving port 44 and reaction viewing port 46. This
allows the blood sample received by the test strip 30 to pass directly from receiving port
44 to viewing port 46. As the sample travels to the viewing port 46 it will encounter
reagent, and any analyte in the sample will begin to react with the reagent and begin to
form an optically detectable condition, such as a color change. This optically detectable
condition is assessed from the viewing port 46, and can be used to determine the
presence of, or calculate the concentration of an analyte of interest. The test strip 30 of
Fig. 2 is illustrative only and many other test strip configurations may be used when
practicing the present invention:
Monitoring meter system 10 of the present invention includes a circuit assembly
physically and electrically connected to a printed circuit board, an example of which is
schematically depicted as the block diagram of Fig. 5. The circuit 100 contains a
microprocessor 102 with a plurality of inputs and outputs. An exemplary embodiment of
the present* invention uses an 8-bit device with 60K of programmable memory. The
microprocessor executes the meter instruction code. The microprocessor receives
input from the user through input device 104, which can include buttons or other input
devices known in the art. A display 106 and a sounder 107 or similar output devices
receives data from the microprocessor for presentation to the user. A memory device
i
108, for example EEPROM, is also connected for input from and output to the
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microprocessor 102. A communication port 110 can also connected in input-output
relationship with the microprocessor in known manner.
A strip sensor 112 receives a drive signal through line 1 14 to turn on and off
photo element 116. The photo element can be an LED. Light from the photo element
1 16 is detected by the photodetector 118. The photodetector can be a photodiode or
phototransistor. Output from the photodetector is supplied via line 120 to the
microprocessor 102. The strip sensor detects when a test strip is inserted into the
meter, and can be initialized by the method described in commonly assigned,
copending US Patent Application / (Atty Docket 0043-00000 entitled
"Improved Method of Strip Insertion Detection"), filed concurrently herewith, the
contents of which are incorporated herein by reference.
The circuit assembly can include a light intensity control circuit, represented as
section 122 of the diagram, and a light detector circuit 124, discussed in further detail
hereinbelow. An exemplary embodiment of the present invention operates using a DC
offset ("virtual ground") of 2.5V reference (not shown) and is powered from a 1 .5V AAA
battery (not shown), which may include a voltage divider circuit or other power
management circuitry as is known in the art.
An analog to digital (A/D) converter 126 converts analog electrical output on line
128 from the light detector circuit 124 into digital information for the microprocessor 102
In an exemplary embodiment of the invention, a 12-bit A/D converter is employed. A
temperature sensor 130 provides a voltage proportional to the temperature along line
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132 to the A/D converter. The microprocessor 102 can make a determination as to
whether the temperature of the testing environment is within predetermined thresholds,
and prohibit a user from running a test if accuracy would be negatively affected.
The light intensity control circuit (LICC) 122 will now be described. In an
exemplary embodiment, the circuit is supplied by a pulse width modulated signal along
line 134 from the microprocessor 102. The circuit includes a low pass filter 136, a
modulator 137, a flux biasing resistor 138, a reference photodiode 140, a control loop
error amplifier 142, a feedback loop compensation capacitor 144, and LED drive
transistors 146. The LICC controls the drive supplied to the LEDs 148, as will be
described.
The LEDs, of which there are two in the exemplary embodiment, generate light, £
component 150 of which will encounter the target 152, which is the test strip or other
test element inserted into the meter. Another component 154 of the light strikes a
chamber reflector 156 and a portion of which 158 is reflected toward reference
photodiode 140. One of the LEDs is a 660nm LED in the exemplary embodiment,
which is appropriate for detecting glucose in a test strip marketed under the tradename
PRESTIGE and sold by Home Diagnostics, Inc. of Ft. Lauderdale, FL. The exemplary
embodiment can be easily modified for detecting other analytes or using other strips by
changing the software and LED used to obtain a different wavelength. For instance, a
580nm LED would be preferred for ketones using known analytical chemistry systems.
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The light detector circuit (LDC) 124 will now be described. In an exemplary
embodiment, the LDC includes a main photodiode 160, a transimpedance (current to
. voltage) amplifier 162, a high pass filter 164, an amplifier 166, and a negative gain
amplifier 168. The output stage of the exemplary LDC includes a demodulator 170, a
level shifting amplifier 172, and a low pass filter 174. The output stage provides a DC
voltage to line 128, as set forth above. The LDC supplies an analog signal to the A/D
converter, which when digitized is interpreted by the microprocessor to provide test
results.
In the exemplary embodiment, input to the A/D converter is conventionally
multiplexed, receiving input from lines 128 and 132, and from other signal lines not
shown and not necessary to understand the present invention.
In the exemplary embodiment, two LEDs are employed, at 610 nm and 660 nm
as described herein. The LEDs are selected according to the instruction code at
appropriate times by the microprocessor 102 by a signal sent via line 176, which
activates a switch 178. If additional LEDs are employed, then additional signal lines
and switches can be added in conventional manner.
The operation of the exemplary circuit 1 00 will now be described. A pulse width
signal is produced by the microprocessor 102 along line 134. As is well known, the
pulse width modulation signal is basically a 2.5V signal delivered either on or off
according to a duty cycle. In a perfect square wave, the duty cycle is 50%, so that the
signal is 50% on, and 50% off. Accordingly, when the signal is on, it is delivered at 2.5
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volts and when it's off, it is zero volts. The signal in line 134 is averaged by the low
pass filter 136 to arrive at a drive voltage for the LEDs, which will in turn determine their
output. For example, for a perfect 2.5V square wave, the average voltage, and thus the
output of the low pass filter 1 36 will be 1 .25V. In this way, the power delivered to the
LEDs can be modified by the microprocessor by changing the duty cycle of the pulse
width modulation signal. To increase the light power, the duty cycle of the signal would
i
be increased.
In the exemplary embodiment, the duty cycle of the pulse width modulation signal
is determined during factory calibration of the meter, and the duty cycle value is
permanently stored in the EEPROM. Of course, periodic calibration routines known in
the art could also be employed. Further, different LEDs may have different preferred
drive requirements, so different duty cycles can be utilized based on the LED in
operation.
The circuit 100 employes a modulation or "chopping" function controlled by the
microprocessor 102. The microprocessor 102 supplies a modulation signal via line 180
to the modulator 1 37 of the LICC and to the demodulator 1 70 of the LDC in synchrony.
The chopping signal is essentially a square wave (on/off) signal supplied to drive the
LEDs at a certain frequency, rather than at constant power, to eliminate noise in the
signal output of the circuit. In the exemplary embodiment, a 2 kHz chop is employed.
The chopping function allows the shifting of the frequency of the light signals LICC
upward to a "quieter" region of the spectrum where ambient light effects can be
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minimized in the LDC. For example, while sunlight is 0 Hz (DC), incandescent lights
have a frequency of 120 Hz. Fluorescent lights are also 120 Hz, but also have
harmonic frequencies. By shifting the drive frequency of the LEDs above that of
ambient light at the LICC, the LDC will be able to receive a signal at the matching
frequency that is above the spectrum where most noise is encountered.
The LICC includes flux biasing resistor 138 which is in parallel with modulator
137. This resistor in parallel essentially inhibits the voltage from the low pass filter 136
from being completely turned off by the modulator 1 37. In this way, the chopping
function, instead of modulating between full-on to full-off will modulate between full-on
and low. The result is that the LEDs will be either full-on or dim, but never completely
off. Several benefits are realized by this arrangement. First, because the LEDs are
never dark, a positive bias is always present at the reference diode 140. As a result,
when interfering ambient light reaches the reference diode 140, there is a tendency for
the modulated signal to move toward ground. This positive bias helps to compensate
for this tendency toward ground and allows the circuit to adapt without a change in
peak-to-peak amplitude by keepfng the modulated signal above ground. Second, the
fact that a voltage is always present maintains control loop error amplifier 142 further
above ground, which promotes better performance.
The control loop amplifier 142, in connection with the compensation capacitor
144 receives the output from the reference photodiode 140 to provide a feedback
mechanism in determining the appropriate drive power for the LEDs 1 48.
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When target 152 is illuminated by light 150 from an LED 148, reflected light 153
is received by the main photodiode 160, producing a photocurrent based on the
reflectance. The photocurrent output of the photodiode 160 is supplied to
transimpedanceamplifier 162, which converts the photocurrent to a voltage. This
voltage is conditioned by high pass filter 164, which removes noise components of the
signal below the chopping frequency. It is here that the noise components of artificial
lighting are filtered out, although certain harmonics of fluorescent light are eliminated
after demodulation by low pass filter 174. In the exemplary embodiment, a 400 Hz
cutoff frequency is employed in high pass filter 164.
The signal emerging from high pass filter 164 is basically a square wave voltage
at the chopping frequency that is nominally 0.5V peak to peak maximum and centered
.*
about the virtual ground of 2.5V. To condition the output for the A/D converter, which in
the exemplary embodiment operates at approximately 2.6V maximum, amplifier 166
and negative gain amplifier 168 are employed as follows. When the LED is on, the top
half of the square wave is connected by level shifting amplifier 172; and when the LED
is off, the bottom half of the square wave is amplified by minus unity and connected by
level shifting amplifier 172. This inverts the bottom half of the square wave when the
LED is off. The demodulator 170 selects between the amplifiers 166, 168 in synchrony
with the modulation occurring in the LIDC at modulator 137. The resulting signal
emerging from demodulator 170 is a DC signal proportional to the reflectance of the
chemistry, in relation to the 2.5V reference voltage in the exemplary embodiment.
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Level shifting amplifier 172, a differential amplifier, receives the DC signal from
the demodulator 170, applies a gain and shifts the signal to a range acceptable to the
A/D converter, which in the exemplary embodiment is approximately 2.6V maximum.
Low pass filter 174 removes spiking introduced by the demodulation of the signal by
amplifiers 166, 168, and also removes a large amount of the harmonics of artificial light
that were shifted high by the demodulation. Further, Any DC offsets in the amplifier
stages prior to the demodulations that were shifted up to the chopping frequency are
also effectively filtered. The only noise left in the signal are harmonics of ambient light
that are right around the chopping frequency, which in the exemplary embodiment of 2
kHz are minimal.
These remaining harmonics are of known frequency and their relationship to the chop
frequency will determine their frequency. For example, the 17 th harmonic of fluorescent
lighting will be 120Hz x 17 = 2040 Hz. If the chop frequency is 2048 HZ, which is more
conveniently generated by binary digital systems than 2000Hz, the strongest remaining
interfering harmonic will be 8 Hz ( |2048Hz - 2040Hz| ). Since this interfering signal is of
known frequency, it can be further reduced by simple synchronous digital filtering
techniques. In countries that use 50Hz power grids, the strongest interfering frequency
will be 2 Hz (the 25 th harmonic of 1 00Hz = 2050Hz, |2048Hz - 2050Hz| = 2Hz). A
simple synchronous digital filtering technique that u nulIs-ouf both 2Hz and 8Hz can be
implemented.
Testing fluid samples for glucose levels according the present invention generally
includes insertion of test strip 30 containing a blood sample into meter system 10 within
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test chamber cover 22 along strip platform 24. Proper insertion of the test strip 30 in
meter system 10 results in locating the reaction viewing port 46 of the test strip 30
directly above the test window (not shown) of meter system 10. Once the test strip is
properly inserted in meter system 10, the 660 nm LED discharges against viewing port
46 of test strip 30, and the reflectance from the discharge is registered by one or more
light detectors. This process continues until the meter system, according to an
algorithm, calculates the glucose level of the sample. A representative algorithm is
described in commonly-assigned copending U.S. Patent Application No. /
(Atty Docket No. 001 1-00000 entitled "Method for Determining the Concentration of an
Analyte on a Test Strip"0), simultaneously filed herewith, the contents of which are
incorporated herein by reference.
The' microprocessor and algorithm software of meter system 10 perform
calculations to arrive at the ultimate glucose measurement. It should be noted,
however, that similar calculations may be used for deriving the amount of other analytes
found in the test strip 30 so long as meter system 10 has been properly reconfigured
and calibrated for the particular analyte of interest.
Meter system 10 according to an illustrative embodiment of the invention is
intended to receive and automatically differentiate between at least three different types
of test elements, as discussed hereinabove. The three types of tests include: (1 ) an
analytical test; (2) a control test; and (3) a standard test. To avoid combining different
types of test results, the results of each test type can be stored in separate locations in
the memory of meter system 1 0. This categorizing of the test results would allow for
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separate recalling of test results for each type of test, but would not combine results
from different types of tests. Access to different types of test results could also be
determined by different protocols, for example allowing a user to view historical
analytical test results, but limiting access to historical standard test results to service
technicians. Alternatively, only the results of certain types of tests could be saved, and
others not saved.
The present invention automatically differentiates between the three different
types of tests by analyzing aspects of the spectral curve derived from reflectance
measurements taken from a test element inserted into the meter system. Aspects of
the spectral curve associated with an inserted test element can be ascertained by
analyzing the percentage of reflectance of the test strip measured over certain
predetermined wavelengths, or a range of wavelengths. An example of a spectral curve
for an analytical element, using whole blood to test for glucose, according to the present
invention and measured between a wavelength range of 500nm to 900nm is illustrated
in Fig. 3.
As illustrated in Fig. 3, the spectral curve of the blood sample forms a generally
concave shape between a wavelength range of 500nm to 800nm, with the lowest
portion of the curve located generally between a wavelength range of 600 to 700 nm. It
has been found that all blood samples applied to the type of test strip described above,
and measured in the manner described above, provide a spectral curve resembling the
that shown in Fig. 3. While the shape of the spectral curve remains similar for all blood
samples irrespective of glucose concentration (Cf. Fig. 5), especially within the range of
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600 nm to 700 nm, the actual reflectance percentages may vary from blood sample to
blood sample. For example, the spectral curve shown in Fig. 3 corresponds to a blood
sample having a high glucose concentration on a PRESTIGE brand test strip, as
depicted by the lowest portion of the curve indicating a 20 to 30 percent reflectance.
Alternatively, the spectral curve for a blood sample having a low glucose concentration
as shown in Fig. 5 will still have its lowest point between the wavelength range of 600 to
700 nm, but with a percentage reflectance above 40.
This vertical displacement of the entire spectral curve for blood glucose tests
presents challenges in differentiating test types, because absolute thresholds are not
easily applied.
As described above, the illustrative embodiment uses a 660 nm wavelength LED
to measure reflectance of a test element inserted into meter system 10. This
wavelength has been selected based on numerous factors, including system
components and type of test strip used, and is designed to correspond with a peak
optical response, e.g., absorbance, of the reaction of analyte with reagent on the test
strip. While the illustrative embodiment contemplates measuring reflectance with a LED
having a wavelength of 660 nm, it is within the scope of the invention that any other
wavelength could be used in association with a different test strip composition or system
components.
Looking again at the spectral curve of the blood sample of Fig. 3, there is
described the optical response over a range of wavelengths for a high glucose sample
applied to a test strip as described by the Carroll patents. Such strips are commercially
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available from Home Diagnostics, Inc., of Ft. Lauderdale, Florida, under the trademark
PRESTIGE SMART SYSTEM. For this glucose reagent system, the reflectance
percentage value (%R) measured at a wavelength of 660 nm is approximately the same
as the reflectance percentage value measured at a wavelength of approximately 610
nm. It was noted by the present inventors that, because as noted above, the shape of
the spectral curve for blood is substantially similar irrespective of glucose level, every
blood sample tested will return similar reflectance percentage values at approximately
610 nm and approximately 660 nm. Although the absolute value of the %R reading
would vary with glucose concentration, the %R measurements at 610nm and 660nm
would always be very nearly the same.
When using a chromogen as an analyte indicator such as with known dry
chemistry 'test strips, the Kubelka-Munk K/S reflectance values can be used to draw a
predictable quantitative relationship between color development and concentration of
the analyte. The spectral curve of the glucose reaction on a given test strip that is
measured is of a known shape and it is known that glucose concentrations can be
calculated using K/S values. The effects of intentionally distorting the spectral curve
shape of the reaction by adding a dye to the glucose control solution can also be
measured using K/S, specifically the difference in K/S values at two different
wavelengths. Therefore, K/S can be used to measure the spectral curve shape of both
a blood glucose and glucose control reaction.
The advantage of using K/S values instead of raw %R in calculations is that
using K/S values tend to provide a more consistent method of measurement from
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varying lots of chemistry strips, which vary from lot to lot. The advantage of using %R is
that it tends to provide a more consistent method of measuring the effect of the dye in
the glucose control solution. As a general proposition, it is easier to control the amount
of dye in the glucose control from lot to lot than it is to control the optical properties of
strips from lot to lot. As a result, K/S can be a more robust means of measuring the
differences in the spectral curve shape from chemistry lot to chemistry lot. However, in
some circumstances, A%R may hold a slight advantage over delta K/S, for example
when measuring low glucose concentrations.
The use of K/S values in an exemplary practice of the present invention is
described in the examples below, where Ch1 is 660nm, and Ch2 is 610nm.
Example 1: %R Method (Glucose Control Detection Using Reflectance)
Glucose Control detected when Ch2 %R is at least 3.5%R less the CM %R at
the conclusion of the test. 1
Pseudo Code
If Ch2 %R <= Chi %R - 3.5%R Then
Glucose Control sample detected
Else
Blood sample detected
Example 2: K/S Method (Glucose Control Detection Using K/S)
Glucose Control detected when Ch2 K/S is at least 0.3 2 less that Ch1 K/S at the
conclusion of the test.
1 Actual %R cutoff value varies with dyes, chromogens and wavelengths used.
2 Actual K/S cutoff value varies with dyes, chromogens and wavelengths used.
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Pseudo Code
If Ch2 K/S <= Chi K/S - 0.3 Then
Glucose Control sample detected
Else
Blood sample detected
Example 3: Gating (Control Detection with Glucose Level Gating)
Glucose control solutions are manufactured at known glucose concentrations.
Certain glucose concentrations can immediately be excluded from the need for spectral
analysis by glucose concentration level alone. For example, blood detection is
indicated, but when final glucose value exceeds 400 mg/dL, control solution is identified,
(n this case, no spectral curve shape analysis would be required.
Pseudo Code
If Final Glucose > 400 mg/dL Then
Blood sample detected
Else
Spectral curve shape must be analyzed to determine
sample, type
In accordance with an illustrative embodiment of this invention, and as described
above, meter system 10 incorporates a second LED having a wavelength of 610 rim.
The second LED operates to measure a second point along the spectral curve of the
test element inserted into the meter. It is this second LED, acting in conjunction with the
strip sensor, that allows the meter system according to the illustrative embodiment to
automatically differentiate between at least the three different types of tests described
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hereinabove to be conducted by meter system 10. The three types of tests are the
analytical test, the standard test, and the control test.
In performing the standard test, a standard strip is inserted into the meter. This
standard strip, as is known in the art, can be formed with a notch in the distal end (the
end first inserted into the meter) so as not to trip the strip sensor upon full insertion.
When inserted, the meter optics will detect the presence of the standard strip because
reflectance values increase (with no test element in place, reflectance is, corrected for
ambient light and noise, statistically equal to zero). Because the strip sensor will not
indicate presence of a test strip because the notch on the standard strip will not trip the
strip sensor, the meter will be able to ascertain that the test element inserted is the
standard test element, and the test run is the standard test.
If the strip sensor is triggered, however, then the meter system will know that a
test strip has been inserted. The test strip is common to both the analytical element and
the control element. Distinguishing between the two, and thus between an actual blood
sample and a glucose control solution, is facilitated by incorporating a dye within the
glucose control solution that alters or distorts the spectral curve, or shape, of the control
element. The dye preferably has a narrow spectral absorbance so that it does not
significantly impact the glucose evaluation of the sample. The distortion of the spectral
curve of the control element due to the dye provides a substantially different reflectance
percentage value measured at 610 nm relative to that at 660 nm. As described above,
the %R values returned at these two wavelengths are very nearly the same in blood.
Accordingly, meter system 10 ascertains that a standardization and verification test
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using glucose control solution is being conducted when the reflectance percentage
values using the 610 nm LED is measurably different relative to the 660 nm LED when
the strip sensor is tripped. The amount of difference between reflectance percentage
values between the 610nm channel and the 660nm channel is dependent on the type
and amount of dye incorporated into the glucose control solution. The type and amount
of dye used should be selected so that it does not exhibit significant absorbance at 660
nm. For example, a dye causing a six point.absolute difference in reflectance
percentage values between measurements by the two LEDs has been found sufficient
to consistently and accurately distinguish the control solution from a blood sample.
Because the dye affects the shape of the curve, the absolute reflectance measurement
is not what is important. What is important is the relative difference between the
reflectance percentages returned between the two wavelengths, which difference would
remain substantially constant irrespective of the absolute values.
Fig. 4 depicts a graph of Percentage Reflectance v. Wavelength comparing the
spectral curve of the blood sample of Fig. 3 (shown in a solid line) with a spectral curve
of a glucose control solution with dye (shown in a dashed line) in accordance with the
present invention. To highlight the method for distinguishing between the samples, the
samples illustrated in the graph have approximately the same glucose concentration.
This is evident from the measured percentage reflectance being approximately the
same for both samples using the 660 nm LED. See point A of the graph of Fig. 4.
As indicated in the graph of Fig. 4 and described above, the spectral curve for
the analytical element (blood) has approximately the same percentage reflectance value
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when measured using both the 610 nm and 660 nm wavelength LED. The spectral
curve for the control element (control solution with the added dye), however, contains a
deflection such that the reflectance percentage value at 610 nm is approximately six
units lower than the reflectance percentage value obtained with a 660 nm LED. Based
on this deflection of the spectral curve resulting from the dye, meter system 10 can be
programmed to distinguish between an analytical element and a control element, and
thus properly select the appropriate test, data processing protocols, display, and related
protocols.
In accordance with the invention, any suitable dye can be used to modify the
spectral curve of the glucose control solution, as long as it produces a detectable
difference in measured results at the two selected LED wavelengths. Appropriate dyes
include Brbmophenol Blue and Crystal Violet. The amount of dye added to the control
solution may be varied, in order to account for various factors understood by one having
skill in the art, such as reagent system performance and monitor apparatus design
considerations. Further, the spectral shape of a fluid sample may be altered by adding
other ingredients which alter measurable optical properties, such as phosphorescing
materials instead of dyes.
A representative control solution is formulated as shown in Table 1 in amounts
sufficient to make 1000 mL of solution.
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Sodium Citrate
WV4IUII 1 VIM UIW
58 80a
GIvCGTOi
40 00a
Sodium Hvdroxids
w UVJIU 1 I 1 1 1 y \J 1 wAIUw
As Nppded
Hydrochloric Acid
As Needed
Acid Red Dve #V
0.50g
Bromophenol Blue
Sodium Salt 2
3.00 g
Glucose
1.85g J
Stabilizers/Preservatives
48.00 g
Deionized Water
Sufficient to total
1000 mL
Azophloxine [CieHi3N3Na 2 08S2]
2 S'^^^'tS^-Tetrabromophenolsulfonephthalein sodium salt [CishfeB^NaOsS]
3
Varies with product target level
Table 1
Distinguishing the type of test being conducted in the meter system in the
manner described above can be performed instantaneously in the case of the standard
test, because the strip sensor is not tripped while reflectance values are being detected
) by the optical block of the monitor apparatus. Distinguishing between the analytical test
and the control test generally takes place after a suitable incubation period has
transpired between the sample fluid and the reagent system, such that reaction
products can be formed and optically detected.
A decision table appears below as Table 2 t summarizing the principles of
5 operation of the illustrative embodiment described hereinabove:
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Test Type
%R
@ 610 nm
@ 660 nm ?
Tripped?
Analytical (blood)
Yes
Yes
Control
No
Yes
Standard
Yes or No
No
Table 2
In accordance with the invention, the above described spectral analysis can be
applied to any type of test strip that has a distinct spectral shape for a given sample
type. Of course, LED wavelengths may be selected from other than 660nm and 610nm,
depending on the reagent system, to allow the meter to both accurately measure the
level of analyte in the sample applied to the test strip, and provide distinguishable
spectral curves between an analytical element and a control element, or even between
different analytical elements. If different analytical elements were to be distinguished
one from another, the reagent system of one type can contain dye particles embedded
in the strip as is known in the art. In this way, tests between, for example, glucose and
cholesterol might be distinguished using the principles described hereinabove. Also,
additional LEDs can be integrated into the optical block, providing an additional data
channel upon which a decision can be based.
Also, as shown above in table 1 , the standard test is the only test which does not
trip the strip sensor, therefore there is no need to ascertain whether the values returned
on the 610nm and 660nm data channels are substantially equal. For example, if the
standard test used a test element where the %R returned at 610nm and 660nm were
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substantially equal, another test type can be provided that would rely on a difference
between 610nm and 660nm. As an example, a cholesterol test strip can have a notch
in its leading edge so as to not trigger the strip sensor, and have a reagent system such
that, at a decision point, there is a measurable relative difference between 610nm and
660nm. The standard test can be further identified by the absolute returns on the
610nm and 660nm channel, for example by providing reflectance values outside the
range returned by analytical or control elements. Once the test type is identified as the
standard test, which can be instantaneous due to the involvement of the strip sensor,
the meter might display %R values instead of analytical values, and the verification by
the user can be.to compare the %R provided with the standard strip with the %R
displayed by the device.
As described above, meter system 10 includes a memory for storing at least
successive final glucose values. The memory may hold a collection of successive final
glucose values, such as, for example, 365 values. With the capacity of modern
subminiature memory chips, a very large amount of data can be reliably stored. These
final values can be recalled by pressing a control button 16. Further, meter system 10
may include a data port or a modem assembly for downloading the stored final glucose
values to another computer system. The computer system receiving the downloaded
final glucose values could be a home PC, or that of a doctor, or a website operator, or
any other person or organization for providing assistance to the user in monitoring their
glucose levels, or for collecting data on diabetes management on a community regional
national or international basis. The modem assembly can be of any configuration (e.g.
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TCP/IP or ATM), or those having wireless communication capabilities (e.g. those using
GSM, WAP, CDMA, etc.). One such modem is described in copending commonly-
assigned US Patent Application No. 09/512,919, filed February 25, 2000, the contents
of which are hereby incorporated by reference.
Other embodiments of the invention will be apparent to those skilled in the art
from consideration of the specification and practice of the invention disclosed herein. It
is intended that the specification and examples be considered as exemplary only, with a
true scope and spirit of the invention being indicated by the following claims.
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WHAT IS CLAIMED IS :
1 . A method for automatically selecting test types in an analytical meter system,
comprising:
providing a test element, said test element belonging to one of a plurality of test
element types;
inserting said test element into an analytical meter system;
measuring a first optical property of the test element;
measuring a second optical property of the test element;
distinguishing said test element by identifying a predetermined relationship
between said first and second optical properties; and
selecting a test type based at least in part upon the results of said distinguishing
step.
2. the method of claim 1 , wherein said plurality of test element types include
analytical elements.
3. The method of claim 1, wherein said plurality of test element types include
control elements.
4. The method of claim 1 , wherein said plurality of test element types include
standard elements.
5. The method of claim 1 , wherein said first and second optical properties are
absorbance at predetermined wavelengths.
6. The method of claim 5, wherein each of said absorbances are measured by
taking at least one reflectance measurement.
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7. The method of claim 6, wherein said predetermined relationship comprises a
relative difference in percent reflectance which is substantially constant.over a
range of measured percent reflectance values.
8. The method of claim 2, wherein said analytical element comprises a biological
fluid.
9. The method of claim 8, wherein said biological fluid comprises a fluid selected
from the set consisting of: whole blood, blood serum, and blood plasma.
1 0. The method of claim 3, wherein said control element comprises a control
solution, said control solution containing a substance for modifying at least
one of said first or second optical properties.
11. The method of claim 1 0, wherein said substance for altering at least one of
said first or second optical properties is a dye.
1 2. The method of claim 1 1 , wherein said dye is selected from the group
consisting of: Bromophenol Blue and Crystal Violet.
13. The method of claim 3, wherein said standard element comprises an element
having known first and second optical properties.
14. The method of claim i; wherein the step of inserting said test element further
comprises the step of automatically either positively or negatively activating a
switch based on the configuration of the test element.
15. The method of claim 14, wherein said selecting step is based at least in part
upon the activation state of said switch.
1 6. The method of claim 1 , further comprising the step of performing the test
selected in said selecting step.
WO 02/071044
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1 7. The method of claim 1 6, further comprising the step of displaying the results
of said test performed in said performing step.
1 8. The method of claim 1 6 further comprising the step of storing data based at
least in part according to the results of said selecting step.
19. The method of claim 18, where said storing step further comprises storing
data classified according to test type.
20 A meter system for performing one of a plurality of test types on a test
element, where the test element is inserted into the meter system and belongs to one of
a plurality of test element types, said meter system comprising:
a first light emitting diode selectively discharging light at a first wavelength;
a second light emitting diode selectively discharging light at a second
wavelengfh;
at least one light detector for measuring light emitted from the first and second
light emitting diodes and reflected from a test element; and
a processor for distinguishing said test element by identifying a predetermined
relationship between said first and second optical properties, and further for selecting a
test type based at least in part upon the results of said distinguishing.
21 . The meter system of claim 20, wherein said test type performed by the meter
system comprises a glucose test performed on whole blood.
22. The meter system of claim 20, wherein the processor distinguishes at least an
analytical element from a control element.
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23. The meter system of claim 20, said meter further comprising a memory for
separately storing results of each test type.
24. The meter system of claim 20, wherein the light discharged from the first and
second light emitting diode has a wavelength within the range of 600nm to 700nm.
25. The meter system of claim 24, wherein the wavelength emitted from the first light
emitting diode has a wavelength of approximately 660nm.
26. The meter system of claim 24, wherein the wavelength emitted from the second
light emitting diode has a wavelength of approximately 61 Onm.
27. A method for distinguishing a control element from an analytical element in a '
meter system, comprising:
programming said meter to recognize a control element formed by applying a
solution sample known to exhibit a first set of reflectance characteristics when
measured within a range of wavelengths;
inserting one of a control element or an analytical element into said meter;
measuring at two predetermined wavelengths a set of reflectance values; and
distinguishing the test element based on the conformity of said reflectance values
obtained by said measuring step with said reflectance characteristics of said control
element programmed in said meter.
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28. A control solution for use in an analytical meter system for measuring optical
properties of a test strip, the control solution comprising a dye intended to modify the
optical properties of the test strip. -
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PCT/US02/05091
12
FIG. 1
WO 02/071044 PCT/US02/05091
FIG. 2
WO 02/071044 PCT/US02/05091
3/6
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PCT/US02/05091
REFLECTANCE VS. WAVELENGTH
80
10
0 I U 1_ 1 _J _i
500 600 700 800 900
nm
FIG. 4
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PCT/US02/05091
FIG. 5
INTERNATIONAL SEARCH REPORT
International application No.
PCT/US02/05091
A CLASSIFICATION OF SUBJECT MATTER
IPq7) :G01N 21/78, 33/52, 35/02
US CL : 422/82.05, 82.08, 82.09; 436/164, 169, 170, 172
According to International Patent Classification (IPC) or to both national classification and IPC
B. FIELDS SEARCHED
Minimum documentation searched (classification system followed by classification symbols)
U.S. : 422/82.05, 82.08, 82.09; 436/164, 169, 170, 172
Documentation searched other than minimum documentation to the extent that such documents are included in the fields
searched
Electronic data base consulted during the international search (name of data base and, where practicable, search terms used)
C DOCUMENTS CONSIDERED TO BE RELEVANT
Category*
Citation of document, with indication, where appropriate, of the relevant passages
Relevant to claim No.
Y
US 5,945,341 A (HOWARD, HI) 31 August 1999, entire document.
1-28
A
US 5,408,535 A (HOWARD, HI et al.) 18 April 1995, entire
document.
1-28
Y
US 3,907,503 A (BETTS et al) 23 September 1975, entire
document.
1-28
A
US 5,520,883 A (CHARLTON et al) 28 May 1996, entire
document.
1-28
A
US 5,789,664 A (NEEL et al) 04 August 1998, entire document.
1-28
A
US 6,027,690 v (GALEN et al) 22 February 2000, entire document.
. 1-28
["I Further documents are listed in the continuation of Box C. See patent family annex.
"0°
Special categories of cited documents: "T"
document defining the general state of the art which is not
considered to be of particular relevance
eaHier document published on or after the international filing date ^
document which may throw doubts on priority claim(s) or which is
cited to establish the publication date of another citation or other
special reason (as specified) "V"
document referring to an oral disclosure, use, exhibition or other
means
document published prior to the international filing date but later
later document published after the international filing date or priority
date and not in conflict with the application but cited to understand
the principle or theory underlying the invention
document of particular relevance; the claimed invention cannot be
considered novel or cannot be considered to involve an inventive step
when the document is taken alone
document of particular relevance; the claimed invention cannot be
considered to involve an inventive step when the document is
combined with one or more other such documents, such combination
being obvious to a person skilled in the art
document member of the same patent family
Date of the actual completion of the international search
03 JUNE 2002
Date of mailing of the international search report
Name and mailing address of the ISA/US
Commissioner of Patents and Trademarks
Box PCX
Washington, D.C. 20231
Facsimile No. (703) 305-3230
Authorized officer J* , / ^ . ^
JEFFREY R. SNAY /^^y^ [ l^'lf ^
Telephone No. (703) 308-0661
Form PCT/ISA/210 (second sheet) (July 1998)*
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